Translation of abstract (English)

Prostate cancer is the second most frequent cause of cancer-related deaths in western countries. Although the incidence of early prostate carcinoma stages increased in recent years, this did not result in a respectively decreased mortality rate because a curative therapy of advanced, metastatic stages does not exist. Elucidation of the biologic processes involved in prostate carcinogenesis provides a basis for the development of novel molecular markers and therapies. By means of microarray technologies an increasing number of candidate genes has been identified. The relevance of these genes in tumour progression and prognosis is validated in large tumour collections e.g. by using tissue microarray technology. In this study tissue microarrays were generated to analyze changes in protein expression during the progression of prostate cancer. To identify new candidate genes of diagnostic and therapeutic relevance, we performed an exhaustive gene search in seven previously described genomic profiling studies with 161 prostate tumours, and four expression profiling studies with 61 tumours. From the resulting list of candidate genes, six were selected for protein expression analysis based on the availability of antibodies applicable for paraffinized tissue: fatty acid synthase (FASN), MYC, beta-adrenergic receptor kinase 1 (BARK1), the catalytic subunits of protein phosphatases PP1a (PPP1CA) and PP2A (PPP2CB) and tumoursuppressor NM23-H1. These candidates were analysed by immunohistochemistry on a tissue microarray containing 651 cores of primary prostate cancer samples and benign prostatic hyperplasias from 175 patients. In univariate analysis, expression of PP1a was found to strongly correlate with the pathological parameter “Gleason score”. MYC immunostaining negatively correlated with both pT-stage and Gleason score in univariate and multivariate analysis. Furthermore, a subgroup of patients with high Gleason scores was characterized by a complete loss of BARK1 protein. In conclusion, this analysis revealed novel molecular markers of potential diagnostic and therapeutic relevance. Finally the potential role of BARK1 in prostate cancer progression was further analyzed in cell lines (BPH-1, 22RV1, LNCaP, PC-3, DU145, HEK, Jurkat). BARK1 specifically desensitizes agonist-bound beta-adrenergic receptors. Therefore, the loss of BARK1 which was observed in advanced tumours is likely to promote an enhanced signal transduction. Modulating the signal transduction intensity by specific agonists (isoproterenol, terbutaline) and antagonists (ICI 118,551, ICI 89,406) of the beta-adrenergic receptors did not influence cell proliferation. However, expression of beta-adrenergic receptor genes was found to be highly upregulated in all prostate cancer cell lines originating from metastases (LNCaP, PC-3, DU145). Furthermore, specific agonists and antagonists influenced beta-adrenergic receptors by further increasing expression of beta-adrenergic receptor genes B1AR and B2AR in PC-3 and DU145, the two cell lines originating from distant metastases. These findings indicate a role of beta-adrenergic receptors in metastasis. If metastasis may be inhibited by beta-blockers has to be elucidated in further studies. In conclusion, the present analysis on tissue microarrays revealed novel molecular markers for prostate cancer progression. Of these, BARK1 might be involved in metastasis formation by regulating beta-adrenergic receptors. These results support the notion to apply beta-blockers in prostate cancer therapy in order to prevent metastasis.